The chronic treatment of Parkinson's disease with levodopa commonly is associated with the development of motor fluctuations and dyskinesias. The reason for these motor effects is unclear, but it is possible that these responses represent the development of tolerance and sensitization to dopaminergic stimulation resulting from chronic drug exposure. This proposal will examine the relationship between alterations in dopaminergic response and the degree of dopaminergic lesioning, the dose and frequency of dopaminergic stimulation, and changes in the content of substance P, a peptide found in the basal ganglia that is thought to modulate dopaminergic neurotransmission. Dr. Gancher has investigated the pharmacology of apomorphine and levodopa in patients with Parkinson's disease and has evidence to suggest the existence of dopaminergic tolerance. The long-term objectives are to obtain training in basic science techniques to allow studies of behavioral, morphological, and biochemical changes in the basal ganglia resulting from chronic treatment, to develop better treatments for motor fluctuations and dyskinesias. This proposal will allow Dr. Gancher to acquire basic science skills and experience to develop his own independent research program that will complement but not duplicate existing research programs at the university. Training in biochemical and animal surgical techniques will be obtained under the supervision of Dr. William Woodward, a neuroscientist with expertise in HPLC using electrochemical detection and brain morphometry. Dr Gajanan Nilaver will provide training in immunohistochemistry, brain mapping, and animal lesioning. Dr. John Crabbe, an authority on ethanol tolerance, will provide guidance in experimental design and interpretation. Dr. John Nutt, a clinical neuropharmacologist and expert in Parkinson's disease will serve as Dr. Gancher's sponsor. Oregon Health Sciences University and affiliated institutions (the Vollum Institute and the Portland VA) has a major interest in the neurosciences and is a robust research environment for additional collaborative studies.